The long term goal of this project is the understanding of disturbances in genome function during the development of cancer. Many specific genes of importance in cancer progression are recognized, but the effects of alterations in these genes on genome function are just beginning to be addressed. The wealth of information available from the human genome sequence can now be applied to this important problem in cancer biology. New technologies are being implemented for this analysis which examine genome function on a large scale. The most advanced of these is microarray technology which allows the simultaneous measurement of gene expression levels for thousands of genes. This technology is currently being applied to the biology of breast cancer, pediatric cancers, melanoma, and adult sarcomas. Our approach integrates analysis of tissue specimens and laboratory models allowing specific pathways to be dissected and related to the disease state. Particular problems of interest include hormone signaling in breast cancer, and the role of specific oncogenes and tumor suppressor genes, especially the fusion oncoprotein transcription factors found in many cancers. From this type of work, we are identifying pathways important for cancer progression, subsets within clinical material, potential new diagnostic and prognostic markers as well as novel candidate therapeutic targets.